Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Thymine DNA glycosylase (TDG) regulates cell cycle–driven p53 transcriptional control in pluripotent cells

ABSTRACT: Cell cycle progression is linked to transcriptome dynamics and variations in the response of pluripotent cells to differentiation cues, through mostly unknown determinants. Here, we characterized the cell cycle–associated transcriptome and proteome of mouse embryonic stem cells (mESCs) in naïve ground state. We found that the thymine DNA glycosylase (TDG) is a cell cycle–regulated co-factor of the tumour suppressor p53. Further, TDG and p53 co-bind ESC-specific cis-regulatory elements and thereby control transcription of p53-dependent genes during self-renewal. We determined that the dynamic expression of TDG is required to promote the cell cycle–associated transcriptional heterogeneity. Moreover, we demonstrated that transient depletion of TDG influences cell fate decisions during the early differentiation of mESCs. Our findings reveal an unanticipated role of TDG in promoting molecular heterogeneity during the cell cycle, and highlight the central role of protein dynamics for the temporal control of cell fate during development.

INSTRUMENT(S): Orbitrap Fusion Lumos, LTQ Orbitrap Velos

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Embryonic Stem Cell

SUBMITTER: Eva Borràs

LAB HEAD: Eduard Sabido

PROVIDER: PXD029596 | Pride | 2023-07-31

REPOSITORIES: Pride

ACCESS DATA

Json Xml

Similar Datasets

Thymine DNA glycosylase regulates cell-cycle-driven p53

Project description:Cell cycle progression is linked to transcriptome dynamics and variations in the response of pluripotent cells to differentiation cues, mostly through unknown determinants. Here, we characterized the cell-cycleassociated transcriptome and proteome of mouse embryonic stem cells (mESCs) in naive ground state. We found that the thymine DNA glycosylase (TDG) is a cell-cycle-regulated co-factor of the tumor suppressor p53. Furthermore, TDG and p53 co-bind ESC-specific cis-regulatory elements and thereby control transcription of p53-dependent genes during self-renewal. We determined that the dynamic expression of TDG is required to promote the cell-cycle-associated transcriptional heterogeneity. Moreover, we demonstrated that transient depletion of TDG influences cell fate decisions during the early differentiation of mESCs. Our findings reveal an unanticipated role of TDG in promoting molecular heterogeneity during the cell cycle and highlight the central role of protein dynamics for the temporal control of cell fate during development.

2023-07-31 | GSE188636 | GEO

Iwamoto2010 - Cell cycle reponse to DNA damage

Project description:After DNA damage, cells activate p53, a tumor suppressor gene, and select a cell fate (e.g., DNA repair, cell cycle arrest, or apoptosis). Recently, a p53 oscillatory behavior was observed following DNA damage. However, the relationship between this p53 oscillation and cell-fate selection is unclear. Here, we present a novel model of the DNA damage signaling pathway that includes p53 and whole cell cycle regulation and explore the relationship between p53 oscillation and cell fate selection. The simulation run without DNA damage qualitatively realized experimentally observed data from several cell cycle regulators, indicating that our model was biologically appropriate. Moreover, the comprehensive sensitivity analysis for the proposed model was implemented by changing the values of all kinetic parameters, which revealed that the cell cycle regulation system based on the proposed model has robustness on a fluctuation of reaction rate in each process. Simulations run with four different intensities of DNA damage, i.e. Low-damage, Medium-damage, High-damage, and Excess-damage, realized cell cycle arrest in all cases. Low-damage, Medium-damage, High-damage, and Excess-damage corresponded to the DNA damage caused by 100, 200, 400, and 800 J/m(2) doses of UV-irradiation, respectively, based on expression of p21, which plays a crucial role in cell cycle arrest. In simulations run with High-damage and Excess-damage, the length of the cell cycle arrest was shortened despite the severe DNA damage, and p53 began to oscillate. Cells initiated apoptosis and were killed at 400 and 800 J/m(2) doses of UV-irradiation, corresponding to High-damage and Excess-damage, respectively. Therefore, our model indicated that the oscillatory mode of p53 profoundly affects cell fate selection.

2020-04-27 | BIOMD0000000939 | BioModels

Mouse Embryonic Stem Cells Resist c-Jun induced Differentiation in Suspension

Project description:The oncogene c-Jun plays a key role in development and cancer. Yet, its role in cell fate decision remains poorly understood at the molecular level. Here we report that c-Jun confers different fate decisions upon mouse embryonic stem cells (mESCs) in adhesion vs suspension. We developed a Tet-on system for temporal induction of c-Jun expression by Doxycycline treatment in mESCs. We show that mESCs carrying the inducible c-Jun TetOn remain pluripotent and grow slowly in suspension with induction of c-Jun, while undergoing differentiation with normal proliferative potentials in adherence upon c-Jun induction. Apparently, c-Jun pushes mESCs in suspension into cell cycle arrest at G1/S, through the induction of Cdkn1a/b and Cdkn2/a/b/c. Despite cell cycle arrest, they can re-enter cell cycle upon plating on adhesive surface and grow into typical mESC colonies albeit at lower efficiency. These results demonstrate that mESCs respond to c-Jun differently in suspension or adherence. Our results suggest that cells in suspension may be more resistant to differentiation than in adherence.

2019-02-19 | GSE114381 | GEO

c-Jun impedes somatic cell reprogramming by activating mesenchymal core regulators and suppressing pluripotent ones

Project description:The somatic cell fate can be converted to tumor or pluripotent ones by ectopic expression of transcription factors in vitro and in vivo. Many oncogenic transcription factors are known to mediate both fates as they share similar proliferative and metabolic properties. Paradoxically, we found c-Jun as the first oncogene that appears to specify a somatic fate, oppose the pluripotent one and impede reprogramming. We performed a series of high through out sequencing to understand the way cJun works. To understand how c-Jun drives mESCs differentiating, we obtained c-Jun TetOn mESCs, and performed RNAseq 36h later with dox inducing or not . To understand why c-Jun blocks reprogramming while c-JunDN and Jdp2 can replace Oct4, we overexpressed these factors with KSM during reprogramming and performed RNAseq 3 Days after virus transfection. Moreover, to extend understand how these factors regulate gene expression, we also overexpressed these factors in MEF and performed RNAseq. Further more, to understand how cJun regulates cell fates and gene expression, we overexpressed c-Jun in mouse ESC and performed ChIP-seq. Also, we performed c-JunDN ChIP-seq during somatic cells reprogramming on day 3, to explore the binding sites of c-JunDN.

2015-06-10 | E-GEOD-50776 | biostudies-arrayexpress

Cell cycle positioning drives heterogeneity within the pluripotent stem cell compartment

Project description:Heterogeneity in pluripotent cells marks a metastable state where cells may drift between native and lineage-primed populations. While the role for these heterogeneities are unclear, they may reflect the dynamic equilibriums of signaling networks and have a direct effect on differentiation potentialities. Here, we report the role of the cell cycle in establishing heterogeneity of human pluripotent stem cells. By utilizing the FUCCI cell cycle indicator system coupled to fluorescent activated cell sorting (FACS), we have uncovered that the cell cycle drives heterogeneity at the epigenetic, transcriptional and post-transcriptional levels. Our data show widespread dynamics in 5-hydroxymethylcytosine (5hmC) during the cell cycle. Furthermore, transcript profiling by RNA-sequencing identified >500 genes that were cell cycle-regulated, of which the largest cohort of genes were transcriptional regulators. In sum, we demonstrate the role of the cell cycle in coordinating cellular transitions between metastable states in pluripotent stem cells. mRNA sequencing of the cell cycle phases; early & late G1, S and G2/S from human ES cells in triplicate.

2013-12-19 | E-GEOD-53481 | biostudies-arrayexpress

Simultaneous profiling of chromatin architecture and transcription in single cells

Project description:Three-dimensional (3D) chromatin structure plays a crucial role in development and diseases, which are associated with transcriptional changes. However, given the heterogeneity in single-cell chromatin architecture and transcription, the regulatory relationship between 3D chromatin structure and gene expression is difficult to explain based on the cell populations. Here we developed a single-cell multimodal omics method for simultaneously detecting chromatin architecture and mRNA expression by sequencing (scCARE-seq). Applying scCARE-seq to examine chromatin architecture and transcription from naïve to primed single mouse embryonic stem cells (mESCs), we observed correlated changes between 3D chromatin structure and expression in the cell fate transition. In addition, we defined cell cycle phase of each cell through chromatin architecture extracted by CARE-seq, and found that periodic changes in chromatin architecture were in parallel with transcription during the cell cycle. These findings indicate that scCARE-seq allows comprehensive analysis of chromatin architecture and transcription in the same single cell.

2023-07-08 | GSE211395 | GEO

Alpha-ketoglutarate links p53 to cell fate during tumor suppression

Project description:Alpha-ketoglutarate links p53 to cell fate during tumor suppression

| PRJNA471027 | ENA

Alpha-ketoglutarate links p53 to cell fate during tumor suppression

Project description:Alpha-ketoglutarate links p53 to cell fate during tumor suppression

| PRJNA470700 | ENA

Wild-type and TP53 genetic knockout BOBSC hiPS cells were maintained in the undifferentiated state or differentiated to definitive endoderm over 72 hours, with or without 5 ppm MMS treatment at 24 hours.

Project description:The ability of human induced pluripotent stem cells (hiPSCs) to differentiate in vitro to each of the three germ layer lineages has made them an important developmental model and tool for tissue engineering. Here we explore the impact of inducing DNA damage at different points during differentiation. We show that, during a critical window in this program, DNA damage diverts cells from an endodermal to mesodermal fate without significant upregulation of an apoptotic program. This change in transcriptional program is driven by p53: cells lacking p53 continue to differentiate towards endoderm with high efficiency despite significant genomic damage and G2/M cell cycle arrest. Thus, DNA damage-induced upregulation of p53 decreases the efficiency of hiPSC differentiation to definitive endoderm by diverting cells towards a mesodermal fate.

2020-07-27 | GSE146225 | GEO

Single-cell time-resolved multi-omics reveal apoptotic and ferroptotic heterogeneity during foam cell formation

Project description:<p>Macrophage-derived foam cell plays a pivotal role in the plaque formation and rupture during the progression of atherosclerosis. Foam cells are destined to divergent cell fate and functions in response to external stimuli based on their internal states, which however is hidden in the traditional studies based on population of cells. Herein, we used time-resolved and single-cell multi-omics to investigate the macrophage heterogeneity along foam cell formation. Dynamic metabolome and lipidome outlined the dual regulating axis of inflammation and ferroptosis. Single cell metabolomics and lipidomics further demonstrated a macrophage continuum featuring a differed susceptibility to apoptosis and ferroptosis. Using single-cell transcriptomic profiling, we verified the divergent cell fate toward apoptosis or ferroptosis. Therefore, the molecular choreography underlying the divergent cell fate during foam cell formation was revealed, which is of high significance for the understanding of the pathogenesis of atherosclerosis and development of new drug targets.</p>

2023-09-08 | MTBLS6366 | MetaboLights

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data